期刊
CELL
卷 162, 期 4, 页码 751-765出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.07.009
关键词
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资金
- NIH NRSA Institutional Postdoctoral Training Grant [T32 AI007019]
- Cancer Research Institute Irvington Postdoctoral Fellowship
- NIAMS, NIH
- Burroughs Wellcome Fund Career Award
- [R37 AI32524]
- [R01 GM0888847]
The RAG1 endonuclease, together with its cofactor RAG2, is essential for V(D)J recombination but is a potent threat to genome stability. The sources of RAG1 mis-targeting and the mechanisms that have evolved to suppress it are poorly understood. Here, we report that RAG1 associates with chromatin at thousands of active promoters and enhancers in the genome of developing lymphocytes. The mouse and human genomes appear to have responded by reducing the abundance of cryptic'' recombination signals near RAG1 binding sites. This depletion operates specifically on the RSS heptamer, whereas nonamers are enriched at RAG1 binding sites. Reversing this RAG-driven depletion of cleavage sites by insertion of strong recombination signals creates an ectopic hub of RAG-mediated V(D)J recombination and chromosomal translocations. Our findings delineate rules governing RAG binding in the genome, identify areas at risk of RAG-mediated damage, and highlight the evolutionary struggle to accommodate programmed DNA damage in developing lymphocytes.
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